THE SAER/S SYSTEM OF S AUREUS: SENSING AND RESPONDING TO INNATE IMMUNITY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 金黄色葡萄球菌(S.aureus)是全球人类感染的主要原因。这种适应性很强的病原体是各种疾病的病原体，从皮肤浅层脓肿到危及生命的疾病。金黄色葡萄球菌对不同环境的适应能力依赖于复杂的辅助基因系统，包括与毒力/致病相关的基因系统。这些辅助基因系统的表达受到转录调控网络的严格控制，包括双组分信号转导系统。然而，在入侵人类宿主的过程中，病原体如何感知和响应不同的环境线索还不是很清楚。因此，Voyich博士的长期目标是更好地了解金黄色葡萄球菌的致病机制。沃伊奇博士的初步研究表明，金黄色葡萄球菌致病的能力在一定程度上是基于它逃避我们先天免疫系统的能力。更具体地说，金黄色葡萄球菌可以避免先天免疫最强大的效应者之一--多形核白细胞(PMN或中性粒细胞)的破坏。根据初步发现，Voyich博士假设金黄色葡萄球菌的双组分调控系统Saer/S触发了病原体保护性反应，以进行天然宿主防御(S)。这一假说基于以下关键观察结果：(1)SAER/S在中性粒细胞吞噬过程中高度上调(86)，(2)在强毒群落相关毒株MW2(脉冲场型USA400)中SAER/S缺失显著降低了PMN吞噬过程中的存活率(3)SAER/S缺失显著降低了脓毒症小鼠模型的毒力。总之，这些数据表明，SAER/S是由中性粒细胞成分(S)触发的，其影响下的基因是中性粒细胞逃避和脓毒症所必需的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Staphylococcus aureus (S. aureus) is a leading cause of human infections worldwide. The highly adaptable pathogen is the causative agent of diverse diseases ranging from superficial skin abscesses to life-threatening diseases. The ability of S. aureus to adapt to varied environments is dependent on complex accessory gene systems, including those involved in virulence/pathogenesis. Expression of these accessory gene systems is tightly controlled by transcriptional regulatory networks, including two-component signal transduction systems. Nevertheless, how the pathogen senses and responds to different environmental cues during invasion of the human host is not well understood. Thus, Dr. Voyich's long-term goal is to gain a better understanding of mechanisms of S. aureus pathogenesis. Dr. Voyich's preliminary studies suggest the ability of S. aureus to cause disease is based in part on its ability to evade our innate immune system. More specifically, S. aureus can avert destruction by one of the most potent effectors of innate immunity, the polymorphonuclear leukocyte (PMN or neutrophil). Based on preliminary findings, Dr. Voyich hypothesizes that the S. aureus two-component regulatory system saeR/S triggers pathogen-protective responses to innate host defense(s). This hypothesis is based on the following key observations: (1) saeR/S was highly up-regulated during PMN phagocytosis (86), (2) deletion of saeR/S in the virulent community-associated strain MW2 (pulse-field type USA 400) significantly attenuated survival during PMN phagocytosis (3) deletion of saeR/S significantly attenuated virulence in a mouse model of sepsis. Collectively, these data suggest that saeR/S is triggered by a PMN component(s) and genes under its influence are necessary for PMN evasion and sepsis.